It has been known that 2-aryl-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane compounds and 2-aryl-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2,4-butanediol compounds, in particular, the compounds in each of which the aryl group at the 2-position is 2,4-difluorophenyl group or 2,5-difluorophenyl group are important intermediates for triazole antifungal agents (Japanese Unexamined Patent Application Publication Nos. 2-191262, 3-128338, 10-306079, and 8-165263 and U.S. Pat. No. 6,300,353).
Examples of processes for producing a 2-aryl-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane compound include:
(1) a production process including 3 steps using stereoselective osmium oxidation of an optically active allyl chloride derivative as a key reaction, the allyl chloride derivative being prepared through 4 steps from L-lactic acid and 1,3-difluorobenzene (Japanese Unexamined Patent Application Publication No. 2-191262);
(2) a production process including a stereoselective addition reaction of a Grignard reagent to an optically active α-keto alcohol derivative and further 3 to 9 steps, the α-keto alcohol derivative being prepared through 6 steps from L-lactic acid and 1,3-difluorobenzene (Japanese Unexamined Patent Application Publication Nos. 2-191262 and 10-212287);
(3) a production process including stereoselective epoxidation of an optically active α-keto alcohol derivative and further 3 steps, the α-keto alcohol derivative being prepared through 3 steps from D-lactic acid (Japanese Unexamined Patent Application Publication No. 10-306079 and U.S. Pat. No. 6,300,353); and
(4) a production process including asymmetric oxidation of an allyl alcohol derivative as a key reaction and further 2 steps, the allyl alcohol derivative being prepared through 7 steps from chloroacetic chloride and 1,3-difluorobenzene, the asymmetric oxidation being developed by Sharpless et al. (Synlett, 1110-1112, 1995).
A 2-aryl-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2,4-butanediol compound is prepared by stereoselective dihydroxylation of a 3-aryl-4-butene-4-alkoxy-1-butene compound as a key reaction and further 3 steps, the 3-aryl-4-butene-4-alkoxy-1-butene compound being prepared through 5 steps from an optically active 3-hydroxy-2-methylpropionate compound (Japanese Unexamined Patent Application Publication No. 8-165263).
A 1,2-epoxy-2-arylbutan-3-ol, which is an optically active 1,2-epoxy alcohol, used as an important material for the above-described 2-aryl-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane intermediate is produced by a known process of stereoselectively oxidizing an allyl alcohol derivative using tert-butyl hydroperoxide in the presence of a metal catalyst, the allyl alcohol derivative being prepared through at least 4 steps from L-lactic acid and an aromatic compound (Japanese Unexamined Patent Application Publication No. 2-191262).
However, a process for producing a (2R,3S)-2-aryl-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2,4-butane diol has problems with safety and cost because an osmium oxide and dicyclohexylcarbodiimide that are known expensive and highly toxic must be used. Furthermore, the process requires 9 steps starting from an easily available material. That is, there has been no simple process.
The process for producing the optically active 1,2-epoxy alcohol must use a peracid as an oxidant, thus disadvantageously resulting in difficulty in mass production in view of industrial safety. Furthermore, the oxidation is a diastereoselective reaction induced by hydroxy group attached to an asymmetric carbon originated from L-lactic acid. Although there are 2 types of diastereomers (threo-diastereomer and erythro-diastereomer), a compound that can be produced by the process is only the erythro-diastereomer. Therefore, to obtain the threo-diastereomer required for producing an intermediate for a triazole antifungal agent, further 2 steps are required to convert the erythro-diastereomer into the threo-diastereomer of the optically active epoxy alcohol.
The above-described known processes for producing the 2-aryl-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane compound serving as an intermediate for a triazole antifungal agent have many industrial practical problems as described below: in process (1), an osmium oxide, which is expensive and highly toxic, must be used; in process (2), an osmium oxide must be used as in process (1), and 10 to 15 steps are required starting from a commercially available material; in process (3), a diastereomeric oxirane compound is prepared by the stereoselective epoxidation of an optically active α-ketoalcohol derivative, but column chromatography is used for purifying the resulting diastereomer; and in process (4), the Sharpless asymmetric oxidation must use tert-butyl hydroperoxide, which is a peracid, as an oxygen source.